Solution-type pharmaceutical composition of phenol derivative, and formulation and use thereof

Abstract

A solution-type pharmaceutical composition of a phenol derivative, and a formulation and use thereof. The pharmaceutical composition comprises the following components: an active ingredient, a humectant, a penetration enhancer, a chelating agent, a pH regulator, and a solvent; wherein the active ingredient is selected from at least one of a compound of formula (I) and a pharmaceutically acceptable salt thereof. The composition has good physical and chemical stability, is suitable for treating autoimmune inflammation, is particularly suitable for treating diseases described above with hair part onset, alleviates the problems of high medication difficulty and poor treatment effect of the hair part, and remarkably improves the medication compliance and life quality of patients.

Description

Solution-type pharmaceutical composition of phenol derivatives, preparation and use thereof

[0001] This application claims priority to a prior application, patent application number 202311450168.8, filed with the State Intellectual Property Office of China on November 2, 2023, entitled “Solution-type pharmaceutical composition of phenol derivatives, formulations thereof, and uses thereof.” The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical compositions, and particularly relates to a solution-type pharmaceutical composition of a phenol derivative, a preparation thereof, and uses thereof. Background Art

[0003] Autoimmune inflammatory diseases, such as psoriasis, atopic dermatitis, and seborrheic dermatitis, are common skin diseases. Psoriasis, commonly known as psoriasis, is a common chronic, inflammatory, systemic disease caused by the interaction of multiple factors, including genetics, environmental factors, and immune factors. It has a long course, is difficult to treat, and is prone to relapse. In some cases, it is almost lifelong and has a significant impact on the patient's physical and mental health. Common sites of disease are the scalp, sacrum, extensor and flexor sides of the limbs, and wrinkles. Nearly two-thirds of patients have lesions in the hair area, especially the scalp, which is a common site for psoriasis. Studies have shown that 50% to 80% of psoriasis patients have skin lesions involving the scalp.

[0004] Seborrheic dermatitis (SD) is a chronic, papulosquamous, superficial inflammatory skin disease that occurs in areas of sebum secretion. The typical rash is dark red or yellow-red macules formed by the fusion of follicular papules, covered with greasy scales or crusts, and may be accompanied by varying degrees of itching. SD is a chronic, recurrent inflammatory skin disease that usually presents as a red, scaly rash. The incidence rate in healthy people is 5%, of which 70.3% occurs on the head, and is common in infants, adolescents and adults. Seborrheic dermatitis refers to a disease of the scalp. This disease differs from simple dandruff in that it has erythema as a sign of inflammation, the scalp is more flaky and sometimes accompanied by itching and burning, and eczema may appear in other parts of the body. The disease can occur in the form of plaques, but often affects the entire scalp and extends beyond the hairline, often including the forehead, around the neck and both ears. In severe cases, the scalp may become secondary infected, with changes that may manifest as a spongy texture, blistering, and crusting, which may ooze. Seborrheic dermatitis also frequently occurs in infancy and typically resolves spontaneously between 8 and 12 months of age. Scalp changes in infants include erythema, flaking, and occasional blisters and crusting. These changes may resolve spontaneously within a few weeks, recur intermittently, or persist throughout childhood. These changes are often accompanied by similar lesions around the eyelids, nose, and ears. The condition then frequently recurs after puberty and can persist throughout life, potentially becoming more severe. Approximately 1-3% of the population suffers from this condition. The etiology and pathogenesis of SD remain unclear, but a complex interplay between Malassezia, keratinocytes, and the immune response plays a crucial role in its development. Seborrheic dermatitis shares some of the same pathogenic factors with inflammatory skin diseases such as atopic dermatitis, such as the regulation of factors that stimulate keratinocyte proliferation and differentiation and disruption of the skin barrier. Atopic dermatitis usually manifests as a Th2 immune response, with elevated levels of interleukin (IL)-4 and IL-13; seborrheic dermatitis is mainly a Th2 and Th17 response, with elevated levels of IL-4, IL-17, and IL-8.

[0005] Current treatments for seborrheic dermatitis include simple anti-inflammatory drugs (such as topical hormone preparations and calcineurin inhibitors) supplemented with skin moisturizing products, but these have low efficacy rates and symptoms are prone to recurrence after drug discontinuation.

[0006] The main purpose of treating psoriasis is to control symptoms and improve the quality of life, and it includes topical medications, systemic medications, and phototherapy. Topical medications are the first-line basic treatment and are suitable for more than 90% of patients. Topical preparations mainly include creams, ointments, gels, etc. However, the commonly used dosage forms of topical medications (creams, ointments, gels, etc.) are difficult to use due to the following reasons: the sebaceous glands of the scalp are dense and active, and the bioavailability of lipophilic creams is affected by the sebaceous glands and hair follicles, resulting in poor therapeutic effects. In addition, due to the obstruction of hair, these preparations will inevitably be applied to the hair during use, which not only causes drug waste, but is also often difficult to wash off, resulting in a greasy appearance and an unpleasant odor, etc., and poor patient compliance. This makes it difficult to use topical medications on the affected areas of the hair and cannot be used effectively.

[0007] Therefore, providing a stable and / or safe pharmaceutical composition / preparation to improve the problems of difficulty in medication, poor therapeutic effect, poor patient compliance, etc. in treating the above-mentioned diseases is something that technicians in this field have long been committed to solving.

[0008] Summary of the Invention

[0009] In order to improve the above technical problems, the present disclosure provides a pharmaceutical composition comprising the following components: an active ingredient, a moisturizing agent, a penetration enhancer, a chelating agent, a pH regulator, and a solvent, wherein the active ingredient is selected from at least one of the compound represented by formula (I) and a pharmaceutically acceptable salt thereof;

[0010] On the other hand, the present disclosure provides a pharmaceutical composition comprising the following components: an active ingredient, a humectant, a penetration enhancer, a chelating agent, a thickener, a pH adjuster, and a solvent, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof;

[0011] In some embodiments of the present disclosure, the pharmaceutical composition is a solution, preferably a solution-type pharmaceutical composition for spray or aerosol administration.

[0012] According to the embodiments of the present disclosure, the compound represented by formula (I) may be an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1):

[0013] According to a preferred embodiment of the present disclosure, the compound represented by formula (I-1) is benvimod.

[0014] According to an embodiment of the present disclosure, the pharmaceutically acceptable salt may be selected from addition salts of the compound of formula (I) and a base.

[0015] In some preferred embodiments of the present disclosure, the pharmaceutical composition contains only the compound represented by formula (I) as the active ingredient, and preferably contains only the E-type isomer represented by formula (I-1) (i.e., benvimod) as the active ingredient.

[0016] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the active ingredient is 0.1 to 8 parts, such as 0.5 to 5 parts, exemplified by 0.5 parts, 0.75 parts, 1 part, 1.5 parts, 2 parts, 3 parts or 4 parts.

[0017] According to an embodiment of the present disclosure, the moisturizing agent is selected from one or more of propylene glycol, glycerin, polyethylene glycol, etc., preferably propylene glycol.

[0018] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the moisturizer is 10 to 35 parts, such as 15 to 30 parts, exemplified by 15 parts, 18 parts, 20 parts, 22 parts, 25 parts, 27 parts or 30 parts.

[0019] According to an embodiment of the present disclosure, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, ethanol, menthol, N-methylpyrrolidone, propylene carbonate and dimethyl isosorbide, preferably diethylene glycol monoethyl ether.

[0020] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the permeation enhancer is 10 to 50 parts, such as 15 to 45 parts, exemplified by 20 parts, 22 parts, 25 parts, 27 parts, 30 parts, 35 parts, 40 parts or 41 parts.

[0021] According to an embodiment of the present disclosure, the chelating agent is selected from metal ion chelating agents, for example, one or more selected from ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; preferably, the salt is a sodium salt, a potassium salt or an ammonium salt; in some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid and / or ethylenediaminetetraacetic acid disodium salt (i.e., disodium edetate).

[0022] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the chelating agent is 0.01 to 1 part, such as 0.05 to 0.5 part, exemplified by 0.05 part, 0.1 part, 0.2 part or 0.5 part.

[0023] According to an embodiment of the present disclosure, the pH regulator is selected from a pH buffer, preferably an organic acid and / or its salt pH buffer, such as one or more of citric acid / sodium citrate buffer, tartrate buffer, oxalate buffer and acetic acid / acetate buffer, preferably citric acid / sodium citrate buffer.

[0024] According to an embodiment of the present disclosure, the solvent is selected from water, preferably purified water.

[0025] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight proportion of the solvent is 20 to 60 parts, for example, 25 to 55 parts, such as 28 parts, 28.75 parts, 30 parts, 35 parts, 40 parts, 45 parts, 47.75 parts, 48.75 parts or 49.25 parts.

[0026] According to an embodiment of the present disclosure, the pharmaceutical composition further optionally contains a thickener; and / or, optionally contains an antioxidant; and / or, optionally contains a preservative.

[0027] According to an embodiment of the present disclosure, the thickener is selected from one or more of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, povidone and polyvinyl alcohol, preferably sodium carboxymethylcellulose.

[0028] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the thickener is 0.01 to 1 part, such as 0.05 to 0.5 part, exemplified by 0.05 part, 0.1 part, 0.2 part or 0.5 part.

[0029] According to an embodiment of the present disclosure, the antioxidant is selected from one or both of propyl gallate and butylated hydroxytoluene (BHT).

[0030] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the antioxidant is 0.01 to 0.2 parts, such as 0.05 to 0.15 parts, exemplified by 0.05 parts, 0.1 parts or 0.12 parts.

[0031] According to an embodiment of the present disclosure, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben and benzalkonium chloride, preferably methylparaben.

[0032] According to an embodiment of the present disclosure, in the pharmaceutical composition, the weight portion of the preservative is 0.01 to 0.3 parts, such as 0.05 to 0.15 parts, exemplified by 0.1 parts, 0.1 parts or 0.15 parts.

[0033] According to an embodiment of the present disclosure, the pH of the pharmaceutical composition is 4 to 6, preferably 4.5 to 5.5, such as 4.5, 5, 5.1, 5.2 or 5.5.

[0034] In some embodiments, the moisturizer and penetration enhancer also serve as a solvent for the compound represented by formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof, an antioxidant and / or a preservative.

[0035] According to an embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of moisturizer, 10 to 50 parts of penetration enhancer, 0.01 to 1 part of chelating agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 20 to 60 parts of solvent, and pH adjuster;

[0036] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;

[0037] Preferably, the pH of the pharmaceutical composition is 4-6.

[0038] According to an embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of moisturizing agent, 10 to 50 parts of penetration enhancer, 0.01 to 1 part of chelating agent, 0.01 to 1 part of thickening agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 20 to 60 parts of solvent and pH adjuster;

[0039] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;

[0040] Preferably, the pH of the pharmaceutical composition is 4-6.

[0041] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5-5 parts of active ingredient, 15-30 parts of moisturizing agent, 15-45 parts of penetration enhancer, 0.05-0.5 parts of chelating agent, 0.05-0.15 parts of antioxidant, 0.05-0.15 parts of preservative, 25-55 parts of solvent, and pH adjuster;

[0042] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;

[0043] Preferably, the pH of the pharmaceutical composition is 4-6.

[0044] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5-5 parts of active ingredient, 15-30 parts of moisturizing agent, 15-45 parts of penetration enhancer, 0.05-0.5 parts of chelating agent, 0.05-0.5 parts of thickening agent, 0.05-0.15 parts of antioxidant, 0.05-0.15 parts of preservative, 25-55 parts of solvent and pH adjuster;

[0045] The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient;

[0046] Preferably, the pH of the pharmaceutical composition is 4-6.

[0047] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of the E-type isomer represented by formula (I-1), 10 to 35 parts of propylene glycol, 10 to 50 parts of diethylene glycol monoethyl ether, 0.01 to 1 part of disodium edetate, 0.01 to 0.2 parts of propyl gallate, 0.01 to 0.3 parts of methylparaben, 20 to 60 parts of water, and a pH regulator; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0048] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of the E-isomer represented by formula (I-1), 10 to 35 parts of propylene glycol, 10 to 50 parts of diethylene glycol monoethyl ether, 0.01 to 1 part of disodium edetate, 0.01 to 1 part of sodium carboxymethylcellulose, 0.01 to 0.2 parts of propyl gallate, 0.01 to 0.3 parts of methylparaben, 20 to 60 parts of water, and a pH regulator; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0049] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5 to 5 parts of the E-type isomer represented by formula (I-1), 15 to 30 parts of propylene glycol, 15 to 45 parts of diethylene glycol monoethyl ether, 0.05 to 0.15 parts of disodium edetate, 0.05 to 0.15 parts of propyl gallate, 0.05 to 0.15 parts of methylparaben, 25 to 55 parts of water, and a pH regulator; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0050] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.5 to 5 parts of the E-type isomer represented by formula (I-1), 15 to 30 parts of propylene glycol, 15 to 45 parts of diethylene glycol monoethyl ether, 0.05 to 0.15 parts of disodium edetate, 0.05 to 0.15 parts of sodium carboxymethylcellulose, 0.05 to 0.15 parts of propyl gallate, 0.05 to 0.15 parts of methylparaben, 25 to 55 parts of water, and a pH regulator; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0051] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer represented by formula (I-1), 30 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 43.75 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0052] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer represented by formula (I-1), 30 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of sodium carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 43.75 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0053] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.5 parts of the E-type isomer represented by formula (I-1), 30 parts of propylene glycol, 41 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 28.25 parts of water and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0054] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.5 parts of the E-type isomer represented by formula (I-1), 30 parts of propylene glycol, 41 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of sodium carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 28.25 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0055] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.5 parts of the E-type isomer represented by formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 49.25 parts of water and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0056] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 0.5 parts of the E-type isomer represented by formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of sodium carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 49.25 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0057] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer represented by formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 48.75 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0058] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 1 part of the E-type isomer represented by formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of sodium carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 48.75 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0059] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 2 parts of the E-type isomer represented by formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 47.75 parts of water and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0060] According to an exemplary embodiment of the present disclosure, the pharmaceutical composition includes the following components in parts by weight: 2 parts of the E-type isomer represented by formula (I-1), 25 parts of propylene glycol, 25 parts of diethylene glycol monoethyl ether, 0.05 parts of disodium edetate, 0.05 parts of sodium carboxymethylcellulose, 0.05 parts of propyl gallate, 0.1 parts of methylparaben, 47.75 parts of water, and a pH regulator, preferably the pH regulator is citric acid / sodium citrate buffer; preferably, the pH of the pharmaceutical composition is 4 to 6.

[0061] Preferably, the total weight of the above components is 100 parts.

[0062] According to an embodiment of the present disclosure, the pharmaceutical composition may further include a second active ingredient.

[0063] The present disclosure also provides a method for preparing the above pharmaceutical composition, comprising mixing the components.

[0064] Preferably, the preparation method comprises the following steps:

[0065] (1) mixing the active ingredient with a moisturizer and a penetration enhancer to form a solution containing the active ingredient;

[0066] Alternatively, the active ingredient, antioxidant, preservative, moisturizer, and penetration enhancer are mixed to form a solution containing the active ingredient;

[0067] (2) mixing a chelating agent, a thickener and a solvent to form a mixed solution; preferably, the chelating agent is first dissolved in the solvent, and then the thickener is added thereto for dispersion and dissolution;

[0068] (3) adding the mixed solution to the solution containing the active ingredient, mixing uniformly, and then adding a pH adjuster to adjust the pH of the system, preferably to 4 to 6;

[0069] (5) adding a solvent to make up the weight to obtain the pharmaceutical composition.

[0070] The present disclosure also provides use of the above-mentioned pharmaceutical composition in preparing a pharmaceutical preparation. Preferably, the pharmaceutical preparation is a solution-type preparation, such as a spray or aerosol.

[0071] The present disclosure also provides a pharmaceutical preparation, preferably a solution preparation, and further preferably a spray or aerosol, containing the above-mentioned pharmaceutical composition.

[0072] According to an embodiment of the present disclosure, in the pharmaceutical preparation, the mass percentage of the active ingredient (i.e., the compound represented by formula (I) and at least one of its pharmaceutically acceptable salts) is 0.1 to 8%, for example, 0.5 to 5%, exemplified by 0.5%, 0.75%, 1%, 1.5%, 2%, 3% or 4%.

[0073] According to an embodiment of the present disclosure, the pharmaceutical composition or pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and / or seborrheic dermatitis;

[0074] Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat seborrheic dermatitis or the above-mentioned diseases occurring in hair-related areas, and is particularly suitable for seborrheic dermatitis or psoriasis occurring in hair-related areas, such as the hair-related areas including but not limited to the scalp and axilla; preferably scalp psoriasis or seborrheic dermatitis.

[0075] The present disclosure provides use of the above-mentioned pharmaceutical composition in the preparation of a medicament for treating and / or preventing an autoimmune inflammatory disease; wherein the autoimmune disease is preferably selected from psoriasis, atopic dermatitis and / or seborrheic dermatitis, more preferably seborrheic dermatitis or psoriasis occurring in the hair area, and most preferably seborrheic dermatitis or scalp psoriasis.

[0076] According to an embodiment of the present disclosure, the pharmaceutical preparation includes a container for containing the pharmaceutical composition. Preferably, the container is a light-proof, airtight container.

[0077] In one embodiment, the pharmaceutical preparation further comprises a spray or aerosol device for spraying the pharmaceutical composition in the form of a spray or aerosol on the affected area. Preferably, the affected area is an affected area with hair, such as but not limited to the scalp and armpits.

[0078] In one embodiment, the pharmaceutical formulation further comprises a propellant.

[0079] In one embodiment, the pharmaceutical composition or the pharmaceutical preparation is administered topically, or is further combined with an oral administration preparation or other topical administration preparation.

[0080] The present disclosure also provides a method for treating autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and seborrheic dermatitis, especially those occurring in hair-bearing areas, comprising administering to a patient an effective amount or a therapeutically effective amount of the pharmaceutical composition or the pharmaceutical preparation.

[0081] The present disclosure also provides use of the pharmaceutical composition in preparing a medicament for treating and / or preventing a disease caused by Pityrosporum ovale; further, the disease is seborrheic dermatitis caused by Pityrosporum ovale.

[0082] The present invention also provides a method for treating and / or preventing diseases caused by Pityrosporum ovale, comprising administering an effective amount or a therapeutically effective amount of the pharmaceutical composition or the pharmaceutical preparation to a patient.

[0083] Definitions and Explanations of Terms

[0084] Unless otherwise indicated, the definitions of terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of this specification.

[0085] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present disclosure sufficient to achieve the intended application (including but not limited to the treatment of a disease as defined below). The therapeutically effective amount may vary depending on factors such as the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on factors such as the specific compound selected, the dosing regimen used, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0086] The term "optional" or "optional" means that the event or environment described below can but does not necessarily occur, and includes both situations where the event or environment occurs and does not occur. For example, "optionally containing an antioxidant" includes both situations where the antioxidant is contained and where the antioxidant is not contained.

[0087] The term "patient" refers to a patient in need of prevention or treatment of a disease associated with anaerobic bacteria, wherein the patient is a mammal, for example, selected from rodents, cows, pigs, dogs, cats and primates, particularly humans. Beneficial effects

[0088] The present disclosure provides a pharmaceutical composition for preparing a spray or aerosol, having good physical and chemical stability. The composition / spray is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis, and seborrheic dermatitis, and is particularly suitable for treating seborrheic dermatitis and the aforementioned diseases that occur in the hair area (such as scalp psoriasis). It has a good therapeutic effect on seborrheic dermatitis and improves the problems of scalp psoriasis such as the difficulty of applying medication to the hair area, poor therapeutic effect, and pain and infection associated with the application of conventional topical medications. It significantly improves patients' medication compliance and quality of life, improves clinical efficacy and safety, and facilitates the long-term management of autoimmune inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] FIG1 is the experimental results of the intradermal retention of Examples 1-5;

[0090] FIG2 is the experimental results of the intradermal retention of Example 4 and the control group;

[0091] FIG3 is the experimental results of the cumulative permeation amount of Example 4 and the control group;

[0092] FIG4 shows the experimental results of the average cumulative permeation amount of Example 4, Example 12 and the control group;

[0093] FIG5 shows the experimental results of skin retention in Example 4, Example 12, and a control group;

[0094] FIG6 shows the clinical effect of Example 12 on the changes in erythema index in treating seborrheic dermatitis;

[0095] FIG7 shows the clinical effect of Example 12 on the change of desquamation index in treating seborrheic dermatitis. DETAILED DESCRIPTION

[0096] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0097] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0098] Examples 1-5

[0099] The prescriptions of Examples 1-5 are shown in Table 1, and the preparation method of the pharmaceutical composition is as follows:

[0100] 1) dissolving the E-isomer of the compound represented by formula (I), methylparaben, and propyl gallate in a mixed solvent of propylene glycol and diethylene glycol monoethyl ether;

[0101] 2) dissolving edetate disodium in purified water, and then dispersing and dissolving sodium carboxymethyl cellulose to obtain a mixed solution;

[0102] 3) preparing a buffer solution of citric acid and sodium citrate;

[0103] 4) adding the mixed solution of step 2) to the drug-containing solution of step 1) and stirring to mix evenly, and adjusting the pH of the system to 4-6 with the buffer solution of step 3);

[0104] 5) Add purified water to make up to the total weight to obtain the pharmaceutical composition.

[0105] Table 1

[0106] Example 6

[0107] The pharmaceutical compositions of Examples 1-5 were prepared into sprays in which the active ingredients were sprayed out in the form of fine mist particles with uniform distribution.

[0108] Example 7

[0109] The pharmaceutical compositions of Examples 1-5 were prepared into aerosols in which the active ingredients were sprayed out as tiny mist particles with uniform distribution.

[0110] Example 8 In vitro skin permeation assay of Examples 1-5

[0111] The intradermal retention of Examples 1 to 5 was tested according to the following method.

[0112] Experimental methods:

[0113] Take the sample of Example 4 and the control group (commercially available Benvimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: In vitro permeation tests were conducted on pig skin (thickness 0.8-1.0 mm) to evaluate the intradermal retention and cumulative permeability. Porcine skin (thickness 0.8-1.0 mm) was mounted on a LOGAN System 918 vertical diffusion cell, exposing 1.77 cm 2surface area. The diffusion cell was connected to a multichannel pump at a speed of 600 rpm, and the receiving fluid was normal saline (0.9% sodium chloride solution). Each cell was placed in a heating manifold to equilibrate the temperature to ensure that the skin surface temperature was 32°C (at least 30 minutes before administration). The sample size was 0.3 g. The receiving fluid was collected at 4, 8, 12, 16, and 24 hours to measure the active ingredient that penetrated through the skin. After the 24-hour sampling period, the skin was wiped with a cotton swab to remove any residual test sample that was considered not to penetrate the skin. The skin layer was cut into pieces and methanol was added for ultrasonic extraction of the drug. The recovered drug concentration was used to calculate the amount retained in the skin.

[0114] The test results are shown in FIG1 , which show that the intradermal retention amounts of Examples 1, 2, and 3 are significantly lower than those of Examples 4 and 5. Therefore, Example 4 was selected as the optimized formula for subsequent screening.

[0115] Example 9 Optimization of Antioxidant

[0116] The antioxidant propyl gallate in Example 4 was replaced with butylated hydroxytoluene to further observe the stability of the new formulation. The specific formulation is shown in Table 2 below:

[0117] Table 2

[0118] a) Stability comparison:

[0119] Equal amounts of the composition of Example 4 and Example 9 were weighed into sealed, light-shielding liquid phase vials, for a total of three sets. These vials were placed at room temperature and 60°C, respectively. The physicochemical stability of the samples was observed and measured using liquid phase chromatography after 0 days, 5 days at 60°C, and 10 days at 60°C. The determination methods for the relevant substances are shown in Table 3-2, and the specific results are shown in Table 3-1. The results showed that new impurities, including RRT2.19, were detected in Example 9 after 5 and 10 days at high temperature, while no new impurities were observed in Example 4, indicating that Example 4 exhibited superior stability compared to Example 9.

[0120] Table 3-1

[0121] Determination method for related substances: use octadecylsilane bonded silica gel as filler; use water as mobile phase A and acetonitrile as mobile phase B, and perform gradient elution according to Table 3-2; the flow rate is 1.0 ml per minute; the column temperature is 30°C; the detection wavelength is 220 nm; the injection volume is 25 μl.

[0122] Table 3-2

[0123] Example 10 Stability Test

[0124] Identical amounts of the composition of Example 4 were weighed into four sets of sealed, light-shielding liquid phase vials. The vials were placed at room temperature, 60°C, and 40°C, respectively. The physicochemical stability of the samples was observed and measured using liquid phase chromatography at 0 days, 60°C for 10 days, 60°C for 30 days, and 40°C for 3 months. The results are shown in Table 4. The results demonstrate that the composition of Example 4 exhibits excellent stability. The testing methods for the relevant substances are as described in Example 9.

[0125] Table 4

[0126] Example 11 Intradermal Retention and Cumulative Permeation Test

[0127] According to the following method, Example 4 and the control group (commercially available Benvimod cream, manufacturer: Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Intradermal retention and cumulative permeation of Benvimod (content: 1%).

[0128] Experimental methods:

[0129] The samples of Example 4 and the control group were subjected to in vitro permeation tests to evaluate the intradermal retention and cumulative permeability. Pig skin (thickness 0.8-1.0 mm) was mounted on a LOGAN System 918 vertical diffusion cell, exposing 1.77 cm 2 surface area. The diffusion cell was connected to a multichannel pump at a speed of 600 rpm and the receiving fluid was PBS (pH 7.4). Each cell was placed in a heating manifold to balance the temperature to ensure that the skin surface temperature was 32°C (at least 30 minutes before administration). The sample was added at a dose of 10 mg of test sample per square centimeter. The receiving fluid was collected at 2, 4, 8, 20, and 24 hours to measure the active ingredient that penetrated through the skin. After the 24-hour sampling period, the skin was wiped with a cotton swab to remove any residual test sample that was considered not to have penetrated the skin. The skin layer was cut into pieces and methanol was added for ultrasonic extraction of the drug. The recovered drug concentration was used to calculate the amount retained in the skin.

[0130] The test results are shown in FIG2 and FIG3 , which show that the intradermal retention amount and cumulative permeation amount of Example 4 are better than those of the control group.

[0131] Example 12 Optimization of thickener

[0132] The applicant considered that the use of thickeners in the prescription may increase the viscosity of the drug solution and may affect the in vitro transdermal effect of the preparation, thereby affecting the patient's compliance with the preparation. The optimized prescription is shown in Table 5:

[0133] Table 5

[0134] The viscosity of the formulation with carboxymethylcellulose sodium added, i.e., Example 4, was significantly increased, and patient compliance was poor; the formulation without carboxymethylcellulose sodium added, i.e., Example 12, could be evenly dispersed on the skin, had low fluidity, and good patient compliance.

[0135] The in vitro transdermal test steps in Example 11 were used to observe the in vitro transdermal conditions of Example 4 and Example 12 (including the average cumulative permeation amount and the skin retention amount per unit mass). The test results are shown in Figures 4 and 5, respectively. It can be seen that the retention amounts of the in vitro transdermal tests of Example 4 and Example 12 are similar, and are slightly higher than those of the control group (commercially available Benvimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: Benavimod content: 1%), while the average cumulative permeation amount of Example 12 (sample without sodium carboxymethylcellulose) was lower than that of Example 4 and the control group, and was only half of that of the control group. Therefore, the safety risk of the sample in Example 12 was reduced.

[0136] Example 13 Stability Test

[0137] The same amount of the composition of Example 12 was weighed into a light-shielded, sealed vial and subjected to accelerated testing (40°C ± 2°C / 75% ± 5% RH). The content determination method is shown in Table 6-2, and the specific results are shown in Table 6-1. The results showed that the composition of Example 12 met the quality standards after six months of accelerated testing and exhibited excellent stability.

[0138] Table 6-1

[0139] The determination method of the relevant substances is as described in Example 9.

[0140] Content determination method: Use octadecylsilane bonded silica gel as filler; use water as mobile phase A and acetonitrile as mobile phase B, and perform gradient elution according to Table 6-2; the flow rate is 1.0 ml per minute; the column temperature is 30°C; the detection wavelength is 220 nm; and the injection volume is 25 μl.

[0141] Table 6-2

[0142] Example 14 Pharmacokinetic Test

[0143] Bama miniature pigs were percutaneously administered with the composition of Example 12 with a benvimod content of 1% and a control group (commercially available benvimod cream, Guangdong Zhonghao Pharmaceutical Co., Ltd., trade name: After the two drugs were tested, the skin pharmacokinetic properties of the common active ingredient benvimod were investigated, and the differences between the two drugs were compared.

[0144] Six Bama miniature pigs (half male and half female) were selected. 10 μL / cm2 of the solution was applied transdermally to the left and right sides of the pigs' back skin. 2 Example 12 Composition and 10 mg / cm 2 After two doses (10-hour dosing intervals) in the control group, skin samples from the dosing area were collected at 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 hours after the last dose (according to the design, dosing was performed at different time points, and the dosing skin was collected when all groups reached the endpoint simultaneously). After wiping the surface ointment with alcohol, the stratum corneum was repeatedly removed with adhesive tape. Skin from a blank area was also collected as the 0-hour point, and the stratum corneum was repeatedly removed with adhesive tape and stored at -20°C. Benvimod concentrations in the skin were determined by HPLC-MS / MS, and PK parameters were calculated using a non-compartmental model using DAS 3.3. Statistical analysis was performed using SPSS.

[0145] The results are shown in Table 7. After the Bama miniature pigs were topically administered with the composition of Example 12 with a bevimod content of 1% and the control group, the exposure of bevimod in the skin of the composition group of Example 12 was about 3.26 times that of the control group, and the AUC (0-t) They were 669±187h*μg / g and 205±39.2h*μg / g respectively.

[0146] Table 7 Pharmacokinetic parameters in the skin of Bama miniature pigs after percutaneous administration of Example 12 / control group

[0147] Note: T max is the median (minimum, maximum).

[0148] Example 15 Sensitization Test

[0149] The Buehler test was performed in adult guinea pigs to evaluate the local sensitization potential of the pharmaceutical compositions of Examples 4 and 5.

[0150] Experimental methods:

[0151] Sixty healthy adult guinea pigs, half male and half female, were randomly divided into a negative control group, a positive control group, a low-dose group (Example 4, 1%), and a high-dose group (Example 5, 2%) according to sex and weight using the TOXSTAT2006 software. The negative and positive control groups each consisted of 10 animals (half male and half female), and the low-dose and high-dose groups each consisted of 20 animals (half male and half female). Before administration, the animals were prepared with electric clippers. The hair on both sides of the dorsal spine was trimmed, leaving a 3×3 cm area on each side. 2 .

[0152] Sensitization: On days 0, 7, and 14, the test substance (0.2 mL / animal) was administered to the left side of the hair removal area. Filter paper was placed in the groove of a blank plaster patch, and the test substance was enclosed in the filter paper and applied to the administration site. The patch was then sealed and secured with non-irritating medical tape. The blank plaster and filter paper were removed approximately 6 hours later. The negative control group received 0.9% sodium chloride injection, while the positive control group received 2% 2,4-dinitrochlorobenzene (ultrasound-treated in 80% ethanol). The low-dose group (Example 4) and the high-dose group (Example 5) received the corresponding concentrations of the Example composition (1% and 2%).

[0153] Challenge: 14 days after the final sensitization, each group of guinea pigs was administered 0.2 ml of the test substance (prepared in 0.2% 2,4-dinitrochlorobenzene in acetone) to the right side of the hairless area. The test substance was removed approximately 6 hours later. Allergic reaction symptoms were observed and recorded 1 hour and 24 hours after sensitization, as well as 24 hours and 48 hours after challenge.

[0154] The results showed that under the experimental conditions, after multiple administration of the composition at different concentrations (1%, 2%) to adult guinea pigs, the Buehler test evaluation results were negative, indicating that as the concentration increased, there was still no sensitization effect on the skin.

[0155] Example 16 Clinical efficacy of seborrheic dermatitis

[0156] In a prospective, randomized, 8-week clinical trial, the spray composition prepared in Example 12 (treatment group) was applied to the skin of subjects with seborrheic dermatitis twice daily. The control group used the base component of Example 12 without benvimod and applied it to the affected area twice daily. Significant improvements in the erythema index and desquamation index of seborrheic dermatitis were observed in the second week and persisted until the eighth week. By the eighth week, the erythema index change in the treatment group had decreased by 81.81%, and the desquamation index change had decreased by 83.70%. In contrast, the erythema index change in the control group had decreased by 38.46%, and the desquamation index change had decreased by 37.44%. Table 8 and Figures 6 and 7 demonstrate the clinical efficacy of the AhR agonist benvimod in treating patients with seborrheic dermatitis.

[0157] Table 8 Clinical efficacy of the spray composition of Example 12 in treating seborrheic dermatitis

[0158] Based on the above experimental results, it can be seen that the pharmaceutical compositions and preparations disclosed herein have good stability, effectiveness and safety in the treatment of autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and seborrheic dermatitis. In particular, sprays and aerosols not only improve the stability of the active ingredients during use and extend the shelf life after unsealing, but also reduce the patient's treatment costs and potential chemical stability risks. In addition, the drugs in the disclosed preparations are sprayed in the form of tiny mist particles, which are evenly distributed and easy to diffuse. At the same time, the irritation to the wound caused by friction during the application process can be reduced, and the pain and infection of local application can be reduced. They are particularly suitable for the treatment of hair-related diseases. These preparations improve patient compliance, improve clinical efficacy and safety, enhance the stability of the drug during use, and contribute to the long-term management of autoimmune inflammatory diseases, preferably psoriasis, seborrheic dermatitis and atopic dermatitis.

[0159] The above describes the embodiments of the present disclosure. However, the present disclosure is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present disclosure shall be included in the scope of protection of the present disclosure.

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition comprises the following components: an active ingredient, a moisturizer, a penetration enhancer, a chelating agent, a pH regulator and a solvent, wherein the active ingredient is selected from at least one of the compounds represented by formula (I) and pharmaceutically acceptable salts thereof; 2. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition is a solution, preferably a solution-type pharmaceutical composition for spray or aerosol administration.

3. The pharmaceutical composition according to claim 1 or 2, wherein The compound represented by the formula (I) is an E-type or Z-type isomer, preferably an E-type isomer represented by the following formula (I-1): Preferably, the pharmaceutically acceptable salt is selected from addition salts of the compound of formula (I) and a base; Preferably, the pharmaceutical composition contains only the compound represented by formula (I) as the active ingredient, and preferably contains only the E-type isomer represented by formula (I-1) as the active ingredient; Preferably, in the pharmaceutical composition, the weight portion of the active ingredient is 0.1 to 8 parts.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The humectant is selected from one or more of propylene glycol, glycerol and polyethylene glycol; Preferably, in the pharmaceutical composition, the weight portion of the moisturizer is 10 to 35 parts; Preferably, the penetration enhancer is selected from one or more of diethylene glycol monoethyl ether, ethanol, menthol, N-methylpyrrolidone, propylene carbonate and isosorbide dimethyl ether; Preferably, in the pharmaceutical composition, the weight portion of the penetration enhancer is 10 to 50 parts; Preferably, the chelating agent is selected from metal ion chelating agents, such as one or more of ethylenediaminetetraacetic acid, sodium gluconate, nitrilotriacetic acid, tartaric acid, citric acid and salts thereof; Preferably, in the pharmaceutical composition, the weight portion of the chelating agent is 0.01 to 1 part; Preferably, the pH regulator is selected from a pH buffer, preferably an organic acid and / or its salt pH buffer, such as one or more of a citric acid / sodium citrate buffer, a tartrate buffer, an oxalate buffer and an acetic acid / acetate buffer; Preferably, the solvent is selected from water; Preferably, in the pharmaceutical composition, the weight portion of the solvent is 20 to 60 parts.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The pharmaceutical composition may further contain a thickener; and / or, may contain an antioxidant; and / or, may contain a preservative; Preferably, the thickener is selected from one or more of sodium carboxymethylcellulose, hypromellose, povidone and polyvinyl alcohol; Preferably, in the pharmaceutical composition, the weight portion of the thickener is 0.01 to 1 part; Preferably, the antioxidant is selected from one or both of propyl gallate and butylated hydroxytoluene; Preferably, in the pharmaceutical composition, the antioxidant is present in an amount of 0.01 to 0.2 parts by weight; Preferably, the preservative is selected from one or more of methylparaben, ethylparaben, propylparaben and benzalkonium chloride; Preferably, in the pharmaceutical composition, the weight portion of the preservative is 0.01 to 0.3 parts; Preferably, the pH of the pharmaceutical composition is 4 to 6; Preferably, the pharmaceutical composition further comprises a second active ingredient.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein The pharmaceutical composition comprises the following components in parts by weight: 0.1 to 8 parts of active ingredient, 10 to 35 parts of moisturizer, 10 to 50 parts of penetration enhancer, 0.01 to 1 part of chelating agent, 0.01 to 0.2 parts of antioxidant, 0.01 to 0.3 parts of preservative, 20 to 60 parts of solvent and pH regulator; The active ingredient is a compound represented by formula (I), preferably the E-type isomer represented by the above formula (I-1) as the active ingredient; Preferably, the pH of the pharmaceutical composition is 4-6.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, wherein: The preparation method comprises mixing the components to obtain; Preferably, the preparation method comprises the following steps: (1) mixing the active ingredient with a moisturizer and a penetration enhancer to form a solution containing the active ingredient; Alternatively, the active ingredient, antioxidant, preservative, moisturizer, and permeation enhancer are mixed to form a solution containing the active ingredient; (2) mixing a chelating agent, a thickener and a solvent to form a mixed solution; preferably, the chelating agent is first dissolved in the solvent, and then the thickener is added thereto for dispersion and dissolution; (3) adding the mixed solution to the solution containing the active ingredient, mixing evenly, and then adding a pH adjuster to adjust the pH of the system, preferably to 4 to 6; (5) adding a solvent to make up the weight to obtain the pharmaceutical composition.

8. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a pharmaceutical preparation; preferably, the pharmaceutical preparation is a solution preparation, such as a spray or an aerosol. Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis and / or atopic dermatitis; Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat the above diseases occurring in hair areas, and is particularly suitable for psoriasis occurring in hair areas, such as hair areas including but not limited to scalp and axilla; preferably scalp psoriasis.

9. A pharmaceutical preparation, wherein The pharmaceutical preparation contains the pharmaceutical composition according to any one of claims 1 to 6; Preferably, the pharmaceutical preparation is a solution preparation, preferably a spray or an aerosol; Preferably, the mass percentage of the active ingredient in the pharmaceutical preparation is 0.1 to 8%; Preferably, the pharmaceutical preparation is used to treat autoimmune inflammatory diseases, preferably psoriasis, atopic dermatitis and / or seborrheic dermatitis; Preferably, the pharmaceutical composition or pharmaceutical preparation is used to treat seborrheic dermatitis or the above diseases occurring in the hair area, and is particularly suitable for seborrheic dermatitis or psoriasis occurring in the hair area; preferably scalp psoriasis or seborrheic dermatitis.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for treating and / or preventing autoimmune inflammatory diseases or diseases caused by Pityrosporum ovale; Preferably, the autoimmune disease is selected from psoriasis, atopic dermatitis and / or seborrheic dermatitis, more preferably seborrheic dermatitis or psoriasis occurring in the hair area, most preferably seborrheic dermatitis or scalp psoriasis; preferably, the disease caused by Pityrosporum ovale is seborrheic dermatitis caused by Pityrosporum ovale.

11. A method for treating autoimmune inflammatory diseases, characterized in that: The method comprises administering to a patient an effective amount or a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 6 or the pharmaceutical preparation of claim 9; The autoimmune inflammatory disease is preferably psoriasis, atopic dermatitis and seborrheic dermatitis, and is further preferably psoriasis, atopic dermatitis and seborrheic dermatitis that develop in the hair area.

12. A method for treating and / or preventing diseases caused by Pityrosporum ovale, characterized in that: The method comprises administering to a patient an effective amount or a therapeutically effective amount of the pharmaceutical composition of any one of claims 1 to 6 or the pharmaceutical preparation of claim 9; Preferably, the disease caused by Pityrosporum ovale is seborrheic dermatitis caused by Pityrosporum ovale.

Images